Enol lactones and lactams bearing a halogen at an endocyclic or exocyclic vinylic position will be prepared as enzyme-activated irreversible inhibitors of serine proteases. Enzyme inactivation would involve the sequence: Acyl transfer of the lactone (or lactam) carbonyl group to the serine hydroxyl group would release a halocarbonyl group within the active site of the protease; during the lifetime of the acyl enzyme intermediate, this group could alkylate a nucleophilic residue near the active site; this alkylation would affix the molecule permanently in a fashion that would block further access of substrate, regardless of whether subsequent deacylation of serine took place. The synthetic accessibility of the prototype haloenol lactones and lactams will be systematically examined, utilizing several approaches: cyclization of acetylenic acids and oxidative ring expansion of cyclic enones. Enzyme inactivation studies will be done with these compounds using trypsin and chymotrypsin to indicate what structural features lead to optimal inhibitors, that is those that have low rates of spontaneous hydrolysis, yet are good enzyme substrates and efficient inactivators. Finally, systems designed to be selective inactivators of specific proteases, particularly those involved in the process of cell transformation and tumor invasion (plasminogen activator and plasmin) will be prepared. These selective inhibitors will be studied in normal and virus-transformed chick embryo fibroblast cultures.